(a) Field
The subject matter disclosed generally relates to oral enzymatic compositions for the treatment of various intestinal diseases.
(b) Related Prior Art
The diamine oxidase (EC 1.4.3.6), also called histaminase, catalyses oxidative deamination of histamine and other biogenic amines, with the release of the corresponding aldehydes, hydrogen peroxide (H2O2) and ammonia (NH3). As previously shown with other copper oxidases, such as ceruloplasmin and bovine serum amine oxidase, with antioxidant properties, diamine oxidase (DAO) of vegetal origin (VDAO), with an enzymatic activity higher than that of the animal DAO, presents some beneficial effects in ischemia and reperfusion injury. Plant histaminase also exhibits a beneficial effect in an anaphylactic response. Furthermore, it was also proposed for the treatment of asthma-like reaction. Recently, it was shown that pea seedling DAO, parenterally administered, may have protective effects on intestinal ischemia, by reducing local tissue inflammation through acceleration of histamine catabolism and by preventing free radical-mediated tissue injury, with significant decrease in tissue levels of peroxidation and nitration products, of DNA damage and of ileal cell apoptosis.
The DAO is also the main histamine degrading enzyme acting predominantly in the intestinal tract. The presence of DAO in the intestinal mucosa may induce a protection against the endogenous or exogenous (food) histamine. The enhancement of histamine content in human could be imputable to various factors. Food-induced histaminosis can generate plasma histamine elevation and haemodynamic alterations, particularly when associated with low DAO activity. A high histamine content in some food can become toxic, especially in certain oriental food. Elevated histamine content in food and beverages can also be associated to microbial contamination. The mechanism of pseudo-allergic reactions of histamine caused by food seems to be mainly ascribed to an intestinal hyperpermeability (caused by irritant species such as alcohol) or by decrease of DAO enzymatic activity. Since DAO is a major catabolic enzyme for histamine in humans, its lower mucosal level at the sites of inflammation would generate an accumulation of the released histamine, which may participate to the induction and enhancement of acute inflammatory responses. Thus, in the pathogenesis of inflammatory bowel diseases (IBD), mucosal alterations are frequently reflected in changes of mucosal DAO activity and, respectively, in mucosal histamine content. Lower tissues levels of DAO activity were found in areas of macroscopically-inflamed tissue in IBD than in normal tissues. The jejunal secretion of histamine was reported as higher in Crohn's disease and was significantly correlated with the Crohn's disease activity index. High histamine content was also found in experimental neoplasias, such as colon carcinomas.
Another factor involved in the pathogenesis of intestinal inflammation is the oxidative stress that can amplify the intestinal inflammation by increasing mucosal and vascular permeability and by recruitment and activation of more neutrophils, with higher release of free radicals and pro-oxidant species. An important component of the endogenous defense against oxidative stress is represented by antioxidant enzymes, such as intracellular superoxide dismutase, catalase, glutathione peroxidase or circulatory ceruloplasmin. Decreased antioxidant enzyme activities or an unbalanced expression of one of these enzymes may increase the vulnerability of cells to reactive oxygen species, hindering recovery of the mucosa, as reported in IBD (Buffinton and Doe, Free Radic Biol Med 1995; 19: 911-918). Thus, to compensate the loss of antioxidant defense, treatments with antioxidants are requested.
Concerning the therapeutically effects of DAO on IBD, Fogel and Lewinski (Inflamm Res 2006; 55: S63-S64) showed a possible therapeutic effect of hog kidney DAO, administrated intra-peritoneally, on a model of ulcerative colitis (UC) in rat, with a reduction of inflammatory reaction. Decreasing the histamine levels and preventing the oxidative stress in intestinal inflammation could be a promising bi-functional therapeutic strategy to better manage the IBD. As for most of oxidases, a by-product of the DAO enzymatic reaction is H2O2, a pro-oxidant agent which can present desirable bactericidal and undesirable oxidative damaging effects. Catalase (EC 1.11.1.6) is an anti-oxidant enzyme that specifically catalyzes the decomposition of H2O2. Due to its capacity to decompose H2O2, catalase was proposed for use in post-ischemic reperfusion injury in myocardial infarction and stroke, burns, trauma, renal transplants, respiratory distress syndrome and broncho-pulmonary displasia (U.S. Pat. No. 5,334,382 to Phillips and Snow) as parenteral formulations of the enzyme covalently bound to polyethylene glycol.
Delivery of bioactive agents to upper intestine and/or colon without gastric or intestinal degradation during the gastro-intestinal transit of the oral dosages represents a major challenge. In this context, the design of biodegradable intestinal delivery systems of bioactive agents for different diseases, such as colon cancer, IBD including Crohn's disease and Ulcerative Colitis, gained increasing interest. Such therapeutic forms that target intestinal sites could improve the treatment of these diseases. As colonic microflora produces a large number of degrading enzymes, several natural polysaccharides from algal (alginates), plant (pectin, guar gum), microbial (dextran, xanthan gum) or animal origin (chondroitin), have been investigated as carriers for colon-specific drug delivery. In addition, colonic delivery could be achieved using pH-dependent matrices or swelling controlled systems. However, when orally administered, therapeutic proteins for intestinal targeting are susceptible to degradation during gastric and intestinal transit. In the stomach, the proteins are affected by acidic and pepsinolytic degradation, whereas in upper intestine, pancreatic and intestinal proteases also generate massive degradation of proteins. Prior art describes various functional coatings based on Eudragit® or pectin excipients formulated as beads or granulates. For example, in US 20080124279, there is proposed a colonic delivery using Zn/pectin beads protected by a functional coating. There is a continuous need to formulate and to orally administrate therapeutic proteins aimed to treat histamine-related dysfunctions.